Our laboratory is interested in the mechanisms through which nociceptive information is transmitted by primary afferents and dorsal horn neurons as well as the neurochemistry of the circuits that regulate this information. Most studies have concentrated on the contribution of the substance P-containing, peptide population of primary afferents C-fiber nociceptors. By contrast, although the number of C-fiber nociceptors that do not express peptides is much greater,, there is no information concerning the type of pain provoked by their activation. These afferents are of particular interest because they exclusively target a group of interneurons in the inner lamina II of the spinal cord dorsal horn. This is very different from the target of the peptide-containing afferents, which includes neurons that project to the brainstem and thalamus. We recently demonstrated that these afferents express the vanilloid-1/capsaicin receptor, and are thus nociceptors. We also demonstrated that the non- peptide, but not the peptide population of afferents, selectively expresses the 5HT-3 receptor. We have therefore used activity at this receptor, which induces pain, as a window into the contribution of the non-peptide population of afferents to nociceptive processing and pain. We have proposed a series of anatomical, behavioral and electrophysiological studies in wild type and 5HT-3 receptor null mice that will address the function of these afferents. Using combined in situ hybridization and immunocytochemistry and immunocytochemistry we will first identify the neurochemical phenotype of the primary afferent neurons that express message for the 5HT-3 receptor. In electron microscopic studies we will examine the central termiantion of the non-peptide afferents. Using behavioral and neuroanatomical approaches we will test the hypothesis that projection neurons in lamina I transmit the "pain" message that is signaled by nociceptive activity in the non-peptide afferents. Finally, we will use an electrophysiological approach in the mouse spinal cord to address the contribution of the non-peptide C-fiber nociceptors to central sensitization and we will test the hypothesis that activity at the spinal 5HT-3 receptor facilitates the transmission of nociceptive messages. Taken together these studies will provide important new insights into the factors that contribute to the development of acute and persistent pain conditions.